Abstract

Sex differences occur in most non-communicable diseases, including metabolic diseases,
hypertension, cardiovascular disease, psychiatric and neurological disorders and cancer.
In many cases, the susceptibility to these diseases begins early in development. The
observed differences between the sexes may result from genetic and hormonal differences
and from differences in responses to and interactions with environmental factors,
including infection, diet, drugs and stress. The placenta plays a key role in fetal
growth and development and, as such, affects the fetal programming underlying subsequent
adult health and accounts, in part for the developmental origin of health and disease
(DOHaD). There is accumulating evidence to demonstrate the sex-specific relationships
between diverse environmental influences on placental functions and the risk of disease
later in life. As one of the few tissues easily collectable in humans, this organ
may therefore be seen as an ideal system for studying how male and female placenta
sense nutritional and other stresses, such as endocrine disruptors. Sex-specific regulatory
pathways controlling sexually dimorphic characteristics in the various organs and
the consequences of lifelong differences in sex hormone expression largely account
for such responses. However, sex-specific changes in epigenetic marks are generated
early after fertilization, thus before adrenal and gonad differentiation in the absence
of sex hormones and in response to environmental conditions. Given the abundance of
X-linked genes involved in placentogenesis, and the early unequal gene expression
by the sex chromosomes between males and females, the role of X- and Y-chromosome-linked
genes, and especially those involved in the peculiar placenta-specific epigenetics
processes, giving rise to the unusual placenta epigenetic landscapes deserve particular
attention. However, even with recent developments in this field, we still know little
about the mechanisms underlying the early sex-specific epigenetic marks resulting
in sex-biased gene expression of pathways and networks. As a critical messenger between
the maternal environment and the fetus, the placenta may play a key role not only
in buffering environmental effects transmitted by the mother but also in expressing
and modulating effects due to preconceptional exposure of both the mother and the
father to stressful conditions.